Therapeutic agents targeting molecular changes are involved in the treatment of several human cancers. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase receptor, is one of the targets in colorectal cancer therapy because of its deregulation in 60% to 80% of the cases. Activated signaling pathways include the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol3-kinase (PI3K)/PTEN/AKT pathway involved in cell proliferation, angiogenesis, apoptosis and metastatic processes (Baselga, J., Eur. J. Cancer 37 Suppl 4 (2001) S16-S22).
Monoclonal antibodies targeting EGFR, like cetuximab (Erbitux®) and panitumumab (Vectibix®) have entered clinical practice and have shown benefit in approximately 10% to 20% of patients with colorectal cancers due to the inhibition of downstream pathways (Amado, R. G., et al., J. Clin. Oncol. 26 (2008) 1626-1634; Cunningham, D., et al., N. Engl. J. Med. 351 (2004) 337-345; Saltz, L B., et al., J. Olin Oncol. 22 (2004) 1201-1208; Van Cutsem, E., et al., J. Clin. Oncol. 25 (2007) 1658-1664). Previous work has shown that mutations in KRAS negatively correlate with the response to anti-EGFR antibodies and therefore are an independent predictive marker of resistance against this therapy (Lievre, A., et al., Cancer Res. 66 (2006) 3992-3995). Based on these results, the European Medicines Agency (EMEA), has approved the use of panitumumab and cetuximab only for patients with metastatic colorectal cancer without activating mutations in KRAS and mutation analyses should be part of the pretreatment. KRAS mutations account for 30% to 40% of the cases resistant to anti-EGFR therapies (Di Fiore, F., et al., Br. J. Cancer 96 (2007) 1166-1169; Lievre, A., et al., Cancer Res. 66 (2006) 3992-3995). Some studies suggested that additional mutations concerning the RAS/RAF/MAPK and PI3K/PTEN/AKT pathway are involved. Patients with wildtype KRAS and mutations in BRAF do not respond to anti-EGFR therapy, whereas wildtype BRAF status seemed to increase the therapy efficiency (Di Nicolantonio, F., et al., J. Olin. Oncol. 26 (2008) 5705-5712). Recently it was shown that BRAF mutations in colorectal cancer are rather of prognostic than predictive value (Tol, J., et al., Eur. J. Cancer 46 (2010) 1997-2009).
The BRAF V600E mutation is one of the most common mutations in human cancer with a high incidence in malignant melanoma (Curtin, J. A., et al., N. Engl. J. Med. 353 (2005) 2135-2147). High objective response rates in melanoma patients carrying this mutation were observed in the phase I clinical trial of the RAF inhibitor PLX4032 and phase II and phase Ill studies are limited to patients with BRAF V600E mutation (Flaherty, K. T., et al., N. Engl. J. Med. 363 (2010) 809-819). Recently it has been shown that patient bearing the BRAF V600K mutation respond remarkably to PLX4032, suggesting that mutation assays for codon 600 should at least include the exchanges V600E and V600K (Bollag, G., et al., Nature 467 (2010) 596-599; Rubinstein, J. C., et al., J. Transl. Med. 8 (2010) 67).
PIK3CA mutations have been described in up to 40% of invasive breast carcinoma, and AKT1 mutations have been found in up to 8% of breast carcinoma (Dunlap, J., et al., Breast Cancer Res. Treat 120 (2010) 409-418). These mutations occur early in breast cancer development and may have implications on the selection of therapeutics targeting the PI3 kinase pathway. Moreover it has been shown in lung cancer that combined inhibition of activated PI3K and MAPK signaling might be clinically beneficial (Sos, M. L., et al., Proc. Natl. Acad. Sci. USA 106 (2009) 18351-18356).